This competing renewal application of the National Center for Infertility Research at the MGH & Northwestern Medical Center proposes to continue the Center's efforts to bring together a traditional excellence in clinical investigation, the new tools of molecular biology, and a contemporary approach to human genetics to examine abnormalities of the hypothalamic-pituitary-gonadal axis causing human infertility. This involves a 3 step process of precisely defining the normative physiology in an area; utilizing these statistically valid normative databases to distinguish new pathophysiologic abnormalities: and integrating these approaches to devise rational therapies. This group has a past history of utilizing these approaches to devise novel treatments in the area of GnRH and its analogues and chosen in the current application to focus upon the modulation of FS secretion by GnRH, sex steroids, the inhibin- activin-follistatin axis, and new transcription factors regulating gonadotropin subunit biosynthesis. Important strengths of the Center contributing to its current high level of productivity include: a) its ability to utilize human models whenever possible; by its capability of examining the most important biologic themes in both sexes while focusing primarily upon the female; c) its complementary expertise in the areas under investigation at 2 Centers: d) it tradition of a long-standing collaborative and collegial relationship; e) its outstanding record of training young investigators in infertility research; and f) its current team of seasoned investigators in the appropriate fields to focus upon human infertility. Only such a juxtaposition of expertise and approaches within a Center program can impart the most important efficiencies to any research program; i.e., enhancing the speed of translation of basic advances into improved care of patients with infertility - the goal of the Center.